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The continued rise in fishmeal prices and the scarcity of fishery resources have led to an increase in the use of plant-based protein sources in compound feed, making mold contamination in compound feed a frequent occurrence. Aflatoxin B1 (AFB1) contamination in aquaculture feed can seriously harm fish growth and liver health; it is extremely toxic, posing an even greater risk to carnivorous fish such as grouper. Lycopene, a natural carotenoid, has antioxidant and anti-inflammatory physiological functions and may act as a functional feed additive to mitigate damage induced by mycotoxins. This study utilized hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) as the experimental model. An 8-week feeding trial was performed to systematically assess the impact of lycopene supplementation at levels of 0, 200, 400, 600, and 800 mg/kg to a basal diet containing 800 μg/kg AFB1 on the fish’s growth performance, antioxidant capacity, liver health, inflammation-related gene expression, and hepatic transcriptome. The results showed that adding 200 mg/kg lycopene to the feed significantly increased the FWB and SGR (p < 0.05) of hybrid grouper. An appropriate amount of lycopene could enhance the antioxidant capacity of serum and liver, significantly increase the activities of catalase (CAT) and superoxide dismutase (SOD), and significantly decrease serum alanine aminotransferase (ALT) activity while increasing albumin (ALB) levels (p < 0.05). An amount of 200 mg/kg lycopene significantly alleviated AFB1-induced hepatocyte vacuolation, steatosis, and inflammatory cell infiltration, while the protective effect of higher doses was weakened. The gene expression results showed that 200 mg/kg lycopene significantly upregulated the expression of antioxidant-related genes such as cat, sod, and nrf-2, and increased the expression level of the anti-inflammatory factor il10 (p < 0.05). The transcriptome analysis identified a total of 621 differentially expressed genes, which were mainly enriched in metabolic pathways, fatty acid metabolism, PPAR signaling pathway, redox process, ferroptosis, NF-κB signaling pathway, and Toll-like receptor signaling pathway. In summary, the addition of 200 mg/kg lycopene to the feed can effectively alleviate the growth inhibition and liver damage caused by AFB1 in hybrid grouper. Its mechanism of action may be related to enhancing antioxidant defenses, improving liver tissue structure, regulating lipid metabolism, and maintaining immune homeostasis. The research results indicate that lycopene can be used as a natural functional feed additive to alleviate AFB1 toxicity in hybrid grouper aquaculture. Full article

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, immune cells, and fibrotic tissue within the arterial wall. Among the immune cells that drive this process, macrophages play a central role by mediating both inflammatory activation and tissue repair. Their polarization into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes determines whether plaque progression or stabilization occurs. S100 proteins, particularly S100A8, S100A9, and S100A12, are critical regulators of macrophage function in atherosclerosis. Acting as damage-associated molecular patterns, these calcium-binding proteins interact with receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR)-4 to sustain inflammatory signaling, promote oxidative stress, and amplify cytokine production within atherosclerotic plaques. Elevated S100 protein levels correlate with increased macrophage infiltration, plaque instability, and heightened cardiovascular risk. Understanding how S100 proteins influence macrophage polarization offers new insights into the mechanisms underlying chronic vascular inflammation. Targeting the S100A8/A9 and S100A12 pathways represents a promising therapeutic strategy to mitigate macrophage-driven inflammation and improve plaque stability. Approaches such as inhibition of S100 protein-receptor interactions, suppression of downstream reactive oxygen species production, and modulation of macrophage polarization toward the M2 phenotype have shown potential in experimental models. This narrative review explores the roles of macrophages in atherosclerosis, the involvement of S100 proteins in both disease progression and macrophage polarization, and the therapeutic implications of targeting S100 protein–mediated immune responses. Together, these findings highlight S100 proteins as a therapeutic target modulating macrophage polarization to attenuate atherosclerotic plaque vulnerability. Full article

Neonatal calf diarrhea (NCD) is one of the most important problems of calf breeding across the world. It causes deaths in calves in the first 10 days of their life, and it is mainly caused by Escherichia coli(E. coli), Bovine Rotavirus (BRV) and Bovine Coronavirus (BCoV). The lack of vaccines with consistently high protective efficacy against the main causes of NCD makes disease control highly challenging. The current study aims to design a multi-epitope mRNA-based vaccine targeting the major pathogens responsible for NCD using immunoinformatic tools and molecular modeling approaches. BRV capsid protein VP6, BCoV Spike glycoprotein and E. coli F5 fimbrial protein were used as antigenic proteins to predict potential epitopes. Fifteen selected epitopes were linked with suitable linkers and conjugated with a built-in adjuvant, resulting in the design of a stable, antigenic and non-allergenic vaccine candidate against NCD pathogens. Furthermore, molecular docking analysis shows strong binding affinity between the vaccine candidate and the bovine toll-like receptors TLR2 and TLR4 at low energy and high stability. Based on these findings, the proposed multi-epitope vaccine represents a promising approach for the prevention and control of neonatal calf diarrhea and provides a solid scientific foundation for future experimental studies to validate its efficacy and safety in vivo. Full article

Initially identified as a hormone linking obesity to insulin resistance, resistin is now recognized as a pleiotropic mediator whose cellular sources and biological functions differ substantially between humans and rodents. Beyond its established roles in metabolic dysfunction and inflammation, emerging evidence suggests that resistin may contribute to tissue remodeling and fibrosis in a context-dependent manner. This review critically synthesizes mechanistic, translational, and clinical evidence across the heart, liver, lung, and kidney. Reported interactions with candidate receptors or binding partners, including adenylyl cyclase-associated protein 1 (CAP1) and Toll-like receptor 4 (TLR4), link resistin-associated signaling to inflammatory, oxidative-stress, and profibrotic pathways that can influence fibroblast activation, hepatic stellate cell responses, extracellular matrix production, and structural tissue remodeling. However, the strength and nature of the available evidence differ markedly among organ systems. Direct profibrotic effects are most strongly supported in cardiac experimental models and selected hepatic systems, whereas pulmonary mechanistic evidence is derived largely from studies of other RELM/FIZZ family members, particularly RELMα/FIZZ1 and RELMβ/FIZZ2, rather than human resistin itself, and renal evidence remains predominantly associative. We, therefore, propose a mechanistic paradigm shift that expands, rather than replaces, the established inflammatory role of resistin. Within this framework, the “fibrotic switch” is presented as a unifying hypothesis whereby persistent resistin-associated signaling may couple chronic inflammatory and metabolic stress to progressive fibrogenic remodeling, requiring further organ-, species-, and cell-specific validation. Defining the relevant cellular sources, receptors, and causal pathways will be essential for evaluating resistin as a biomarker and potential therapeutic target in fibrotic disease. Full article

The gut–immune–metabolic axis has emerged as a central regulator of human health, with growing evidence indicating that microbiota-derived metabolites improve gut microbial ecology, enhance intestinal barrier integrity, reduce systemic inflammation, and maintain metabolic homeostasis. This review synthesizes current mechanistic and clinical evidence on the role of postbiotics in regulating intestinal barrier integrity, immune responses, oxidative stress, and metabolic–endocrine homeostasis. The literature was identified through the PubMed/MEDLINE, Scopus, and Web of Science, integrating evidence from experimental, mechanistic, animal and clinical studies on the therapeutic potential of postbiotics to modulate the gut–immune–metabolic axis. Preclinical studies suggest that postbiotics may enhance epithelial barrier function by improving tight junction integrity through multiple pathways such as PI3K/Akt signaling, stimulating mucin-2 (MUC2) production, and reducing intestinal permeability. They modulate immune responses through interactions with Toll-like receptors, nucleotide-binding oligomerization domain receptors, and G-protein-coupled receptors (GPR41/43), influencing key signaling pathways, including NF-κB and Nrf2, and altering cytokine profiles, such as IL-10, TNF-α, and IFN-γ. Similarly, preclinical investigations have demonstrated that short-chain fatty acids (SCFAs) and other microbial metabolites may improve insulin sensitivity, regulate hepatic gluconeogenesis, stimulate glucagon-like peptide 1 (GLP-1) secretion, and modulate lipid metabolism through the FXR and TGR5 signaling pathways. Emerging human studies suggest potential benefits of postbiotics in regulating gut, immune, and metabolic health; nevertheless, clinical evidence remains limited and is influenced by variability in postbiotic composition, dosage, formulation, and metabolite profiles. Therefore, standardized production approaches and well-designed large-scale randomized clinical trials are required to confirm therapeutic efficacy and establish evidence-based applications of postbiotics. Full article

Inflammation plays a pivotal role in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury, highlighting inflammation suppression as a critical therapeutic strategy. The inflammatory response is largely mediated through Toll-like receptor 4 (TLR4), a transmembrane signal receptor whose expression is upregulated by Heat Shock Protein Family A Member 8 (HSPA8). Here, we investigated whether SEM1, a subunit of the 26S proteasome, interacts with HSPA8 and attenuates TLR4-mediated inflammation. Our results demonstrate that SEM1 expression is downregulated following myocardial I/R. Overexpression of SEM1 alleviated cardiac injury and dysfunction, inhibited myocardial inflammation, and downregulated HSPA8 expression in the I/R-injured heart. Co-IP assays confirmed a strong physical interaction between SEM1 and HSPA8, while the precise molecular mechanism responsible for SEM1-induced downregulation of HSPA8 remains to be fully elucidated. Mechanistically, SEM1 suppressed the activation of the TLR4/MyD88/NF-κB signaling pathway. Collectively, these findings identify SEM1 as a novel regulator that protects against myocardial I/R injury via its association with HSPA8 and inhibition of the TLR4-mediated inflammatory cascade, offering a promising therapeutic target for this condition. Full article

Extracellular traps (ETs) are a novel host defense mechanism used to immobilize and eliminate invading microorganisms, and their formation depends on the recognition of foreign pathogens by membrane receptors. Previous studies have demonstrated that Vibrio splendidus flagellin can induce the release of ETs in coelomocytes of the sea cucumber Apostichopus japonicus, yet the underlying regulatory mechanism remains unclear. Here, we identify another Toll-like receptor (TLR) homolog, AjTLR2, in Apostichopus japonicus, which is composed of an extracellular LRR domain, a transmembrane domain, and an intracellular TIR domain. As a membrane receptor, AjTLR2 is upregulated upon infection with Vibrio splendidus AJ01, which is isolated from diseased Apostichopus japonicus. The extracellular LRR domain exhibits binding activity toward LPS, PGN, and MAN. In addition to these ligands, AjTLR2 recognizes flagellin C of AJ01 (AJ01-FliC), whereas other AjTLRs, such as AjToll and AjTLR3, do not. Further functional analysis reveals that knockdown of AjTLR2 results in a reduction in the typical weblike DNA structures of ETs, accompanied by a significant decrease in the expression of the ET-associated antimicrobial proteins H2A, H2B, and lysozyme. Furthermore, AjTLR2 knockdown similarly inhibits ET formation induced by recombinant AJ01-FliC protein. Mechanistically, the Apostichopus japonicus proto-oncogene tyrosine-protein kinase Src homolog (AjSRC), previously identified in our laboratory, is a downstream signaling molecule of AjTLR2 and is recruited via the TIR domain of AjTLR2. Knockdown of AjSRC also suppresses AJ01-FliC-induced ET formation. Collectively, our results indicate that the recruitment of AjSRC by AjTLR2 represents a potential regulatory pathway for AJ01-FliC induced ET generation. Full article

Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by lymphocytic infiltration and dysfunction of the exocrine glands, with manifestations extending beyond glandular sicca symptoms to multiple extraglandular systems. Although the pathogenesis of SjD remains incompletely understood, growing evidence indicates that a complex cytokine network involving both innate and adaptive immune pathways plays a central role in disease development. This narrative review summarizes recent updates on cytokine signaling in SjD across three clinically relevant domains. In glandular inflammation, activation of salivary gland epithelial cells through Toll-like receptor pathways triggers type I interferon (IFN) signaling via plasmacytoid dendritic cells, while IFN-γ, Th17-related cytokines (IL-6, IL-17, IL-22), BAFF/APRIL, and chemokines (CXCL10, CXCL12, CXCL13) collectively sustain local inflammation and ectopic lymphoid organization. The BAFF/APRIL axis, a systemic type I IFN signature, and IL-21–follicular helper T cell–B cell interactions primarily drive systemic immune activation, which together underlie autoantibody production, hypergammaglobulinemia, and a lymphoma-prone phenotype. In contrast, constitutional symptoms such as fatigue, pain, and dryness frequently dissociate from classical inflammatory activity and are better explained by neuroimmune–metabolic mechanisms, including the IFN-γ–IDO–kynurenine pathway and symptom-associated proteomic signatures. Collectively, these findings underscore the heterogeneous nature of SjD, in which glandular inflammation, systemic immune activation, and constitutional symptoms are driven by distinct yet partially overlapping cytokine pathways. Recognizing this heterogeneity has direct implications for cytokine-targeted therapy, suggesting that future trials should stratify patients by disease phenotype (IFN-high, B cell-dominant, and symptom-dominant) rather than treating SjD as a uniform population. Full article

The endocannabinoid system (ECS) is increasingly recognized as a central regulator of immune homeostasis, integrating neural, metabolic, and immune signaling to maintain physiological equilibrium. This Perspective examines the “therapeutic paradox” of endocannabinoid immunomodulation, whereby anti-inflammatory and tissue-protective effects are mechanistically linked to transient immunosuppression. Although cannabinoid receptor 2 (CB2) is the primary mediator of immune regulation, growing evidence indicates that cannabinoid receptor 1 (CB1) also contributes to inflammatory control in both the central nervous system and peripheral tissues. Activation of CB2 suppresses inflammatory signaling through Gi/o-mediated inhibition of adenylate cyclase, reduced cyclic adenosine monophosphate (cAMP) signaling, and repression of nuclear factor kappa B (NF-κB)-dependent transcription. While these mechanisms limit pathological inflammation and promote tissue protection, they simultaneously attenuate innate and adaptive immune functions required for effective pathogen clearance. Across neuroinflammatory disorders, inflammatory bowel disease, hepatic injury, sepsis, cancer, and systemic inflammatory syndromes, the ECS shifts immune responses toward resolution at the cost of reduced antimicrobial readiness. We synthesize the molecular mechanisms underlying this therapeutic paradox, including macrophage polarization, lymphocyte reprogramming, and tissue-specific immune adaptations, and discuss strategies for developing endocannabinoid-based therapeutics that preserve anti-inflammatory efficacy while minimizing immunosuppressive liabilities. Full article

This review covers published data (mostly from 2019 to 2025) on the synthesis and biological activity of azolo[a]quinoxalines, including pyrazolo-, imidazo- and triazolo-annelated systems. We highlight that most research efforts are directed toward the design of anticancer agents, with additional applications as Toll-like receptor antagonists, monoamine oxidase inhibitors, opioid receptor modulators, PI3Kα inhibitors, tubulin polymerization inhibitors, GABAᴀ receptor modulators, VEGFR-2 kinase inhibitors, BRD9 binders, and anti-inflammatory, antimicrobial, and antifungal agents. Recent synthetic strategies include Cu-catalyzed oxidative annulations, I₂-mediated C–H functionalization, metal-free cascade cyclization, and multicomponent reactions, often employing eco-friendly catalysts and reductants. A growing number of studies integrate virtual screening, molecular docking, and pharmacophore-based in silico approaches to guide lead discovery and optimization. Innovative drug delivery systems, such as nanogels and hybrid molecules combining azoloquinoxalines with pharmacophores like thalidomide, have also been explored. This review emphasizes both the medicinal chemistry aspects of azolo[a]quinoxalines and the synthetic methodologies for their preparation from the perspective of drug development and discovery. Full article

In this study, we investigated the protective effects of CPP-C3M4 against Salmonella-induced hepatic injury in lambs. Thirty 72-day-old Hu sheep were randomly divided into five groups: the control group (CON), the Salmonella-infected group (ST), and three CPP-C3M4 pretreatment groups at low, medium and high doses (CPP-C3M4-L, CPP-C3M4-M, and CPP-C3M4-H). The results showed that administration of CPP-C3M4 via duodenal fistula significantly alleviated liver enlargement and histopathological damage caused by Salmonella infection. CPP-C3M4 improved liver function by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride (TG) levels. It enhanced the liver antioxidant capacity by increasing glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities. It also alleviated inflammatory responses by downregulating the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), toll-like receptor 2 (TLR2), and toll-like receptor 9 (TLR9). Transcriptomic Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis further confirmed that CPP-C3M4 exerts its protective effects by suppressing multiple inflammatory pathways, with the interleukin-17 (IL-17) signaling axis being a key target of regulation. These results indicate that CPP-C3M4 is a promising alternative antimicrobial substance for preventing and alleviating Salmonella-induced liver injury in lambs. Full article

Gastric cancer is strongly associated with chronic inflammation and dysregulated immune signaling. Molecules involved in purinergic and innate immune pathways, including Toll-like receptor 3 (TLR3), P2Y purinoceptor 2 (P2RY2), and pannexin-1 (PANX1), may contribute to gastric cancer biology; however, their combined clinical relevance remains unknown. This study included 45 patients with gastric cancer and 45 healthy controls. The gene expression levels of TLR3, P2RY2, and PANX1 were analyzed using RT-PCR, and serum protein concentrations were measured using ELISA. Group comparisons, logistic regression, and ROC analyses were performed to evaluate the diagnostic performance. TCGA-STAD-based immune infiltration analyses were conducted using the TIMER platform, and prognostic significance was assessed using Kaplan–Meier survival analysis. Although alterations in gene expression were observed, none reached statistical significance. At the protein level, PANX1 was significantly elevated in patients with gastric cancer and was independently associated with disease status, whereas TLR3 and P2RY2 showed no significant circulating alterations. TIMER analysis demonstrated positive correlations between TLR3 and PANX1 expression and several immune cell populations, whereas P2RY2 expression showed predominantly negative correlations with immune cell infiltration. Kaplan–Meier analysis revealed that high PANX1 and TLR3 expression levels were associated with improved overall survival. ROC analyses indicated limited diagnostic accuracy for each marker. Collectively, our experimental findings provide evidence only for elevated circulating PANX1 in patients with gastric cancer. In contrast, the observations regarding TLR3 and P2RY2 were not statistically significant in our cohort and should therefore be considered exploratory and hypothesis-generating. Complementary bioinformatic analyses suggest that these molecules may participate in immune-related signaling pathways in gastric cancer; however, these observations require validation in independent tissue-based and larger prospective studies. Full article

Rosacea is a chronic inflammatory skin disorder driven by dysregulated cathelicidin processing and excessive LL-37, which triggers a circuit involving Toll-like receptor 2 (TLR2)/kallikrein-5 (KLK5)-dependent amplification and downstream mechanistic target of rapamycin complex 1 (mTORC1), NF-κB, and NLR family pyrin domain containing 3 (NLRP3) inflammasome pathways. We hypothesized that poly-D,L-lactic acid (PDLLA) could attenuate this inflammatory cascade by inducing macrophage-derived interleukin (IL)-10. PDLLA increased IL-10 secretion from THP-1-derived macrophages in a dose-dependent manner. In LL-37-stimulated HaCaT keratinocytes, LL-37 decreased phosphorylated signal transducer and activator of transcription (pSTAT3)/STAT3, DNA damage-inducible transcript 4 (DDIT4), and phosphorylated AMP-activated protein kinase (pAMPK)/AMPK while increasing phosphorylated protein kinase B (pAKT)/AKT and mTORC1 activation; conditioned media from PDLLA-treated macrophages (CM_PDLLA) restored pSTAT3/STAT3, DDIT4, and pAMPK/AMPK, reduced pAKT/AKT, and suppressed pmTOR/mTOR. CM_PDLLA attenuated downstream inflammatory responses, including NF-κB nuclear translocation, VEGF production, and NLRP3-inflammasome-mediated IL-18 secretion. These findings were validated using an intradermal LL-37-injected mouse model. Compared with the normal control/saline group, LL-37/saline decreased IL-10, pSTAT3/STAT3, DDIT4, and pAMPK/AMPK while increasing pAKT/AKT, pmTOR/mTOR, pS6K/S6K, TLR2/KLK5/LL-37, NF-κB, VEGF, and NLRP3 inflammasome/IL-18 signaling; PDLLA partially restored the STAT3/DDIT4–AMPK regulatory pattern and suppressed these disease-associated signals. Consequently, PDLLA treatment led to a pronounced reduction in clinical lesion area. Overall, PDLLA may attenuate LL-37-driven cutaneous inflammation by promoting an IL-10-linked STAT3/DDIT4–AKT/AMPK program that suppresses mTORC1 and disrupts cathelicidin amplification, supporting its potential as an injectable immunomodulatory approach for rosacea-like skin inflammation. Full article

The ubiquitin ligase protein tripartite-motif containing 56 (TRIM56) positively regulates Toll-like receptor-3 (TLR3) signaling by forming a complex with Toll-Interleukin-1 receptor domain-containing adapter protein inducing interferon (IFN)-beta (TRIF), independent of its E3 ligase activity. Whether TRIM56 modulates other TLR pathways in innate antiviral immunity, however, is unclear. Herein, we show ectopic expression of TRIM56 augments activation of IFN regulatory factor-3 (IRF3)-dependent promoters following stimulation by lipopolysaccharide (LPS) in HEK293-TLR4-MD2-CD14 cells while leaving activation of NF-κB-dependent promoter unaffected, suggesting TRIM56 specifically promotes immune signaling through the TLR4-TRIF axis but not the MYD88 arm downstream of this TLR. Confirming its impact on endogenous antiviral responses in immune sentinel cells naturally harboring the TLR4 pathway, we demonstrated enforced expression of TRIM56 enhanced LPS-induced expression of IFN-beta and IFN-stimulated genes (ISGs) and establishment of an antiviral state in bone marrow-derived macrophages. Importantly, depletion of endogenous TRIM56 impaired LPS-induced antiviral gene expression and cellular antiviral defense. Altogether, these data add to understanding of the role of TRIM56 in TLR-mediated innate immune responses. Given that TRIM56 is an ISG and that many immune adjuvants and some viral proteins activate TLR4, the findings of this study could have implications for designing immunotherapies, especially those against viral infections. Full article

Diabetic kidney disease (DKD) remains one of the most severe microvascular complications of type 2 diabetes mellitus (T2DM) and a leading cause of chronic kidney disease (CKD) worldwide. Nevertheless, despite considerable progress in elucidating its molecular background, early diagnosis and accurate stratification of disease progression remain challenging when relying on conventional clinical biomarkers such as albuminuria and estimated glomerular filtration rate (eGFR). Growing evidence indicates that DKD is driven by interconnected pathogenic mechanisms, including chronic hyperglycemia, activation of the protein kinase C (PKC) signaling pathway, renin–angiotensin–aldosterone system (RAAS) dysregulation, oxidative stress, inflammatory cascades, and immune system activation involving Toll-like receptors (TLR) and the NLRP3 inflammasome. These processes collectively contribute to endothelial dysfunction, podocyte injury, extracellular matrix accumulation, and progressive renal fibrosis. Exosomes and their molecular cargo, particularly miRNAs, have emerged as promising regulators and non-invasive biomarkers reflecting ongoing renal injury. Urinary exosomal microRNAs (uEV-miRNAs) are of interest due to their stability in biological fluids and their direct origin from nephron segments, enabling real-time reflection of renal pathophysiology. Accumulating studies suggest that differentially expressed microRNAs (miRNAs), including miR-21-5p, miR-30a-5p, miR-192-5p, and miR-142-3p, are closely associated with key pathways in DN. However, their clinical translation remains limited by methodological heterogeneity, the lack of standardized isolation protocols, and insufficient validation in large longitudinal cohorts. This review navigates the current landscape of knowledge on the molecular mechanisms underlying DKD and examines the emerging role of uEV-miRNAs as diagnostic biomarkers. Altogether, uEV-miRNAs offer a promising avenue for improving early detection, risk stratification, and disease monitoring in DKD. Full article